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There are distinct cell subpopulations in normal epithelial tissue, including stem cells, progenitor cells, and more differentiated cells, all of which have been extensively studied for their susceptibility to tumorigenesis. However, normal cells usually have to progress through a precancerous lesion state before becoming a full-blown tumor. Precancerous early lesions are heterogeneous, and the cell subset that is the primary source of the eventual tumor remains largely unknown. By using mouse models that are tailored to address this question, we identified a keratin 6a-expressing precancerous stem cell (PcSC) subset and a more differentiated whey acidic protein-positive (WAP+) cell subset in mammary precancerous lesions initiated by the Wnt1 oncogene. Both cell subsets rapidly progressed to cancer upon introduction of constitutively active versions of either HRAS or BRAF. However, the resulting tumors were dramatically different in protein profiles and histopathology: keratin 6a+ precancerous cells gave rise to adenocarcinoma, whereas WAP+ cells yielded metaplastic carcinoma with severe squamous differentiation and more robust activation of MEK/ERK signaling. Therefore, both stem and non-stem cells in mammary precancerous lesions can contribute to the eventual cancers, but their differentiation status determines the resulting cancer phenotype. This work identifies a previously unknown player in cancer heterogeneity and suggests that cancer prevention should target precancerous cells broadly and not be limited to PcSC. SIGNIFICANCE: This work uses a novel mouse mammary gland cancer model to show that tumors initiated from different precancerous mammary epithelial cells are distinct.

Mammary Precancerous Stem and Non-Stem Cells Evolve into Cancers of Distinct Subtypes